CN111875605B - Preparation and application of bisamide compound containing substituted pyrazole and beta-carboline units - Google Patents
Preparation and application of bisamide compound containing substituted pyrazole and beta-carboline units Download PDFInfo
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- CN111875605B CN111875605B CN202010867590.3A CN202010867590A CN111875605B CN 111875605 B CN111875605 B CN 111875605B CN 202010867590 A CN202010867590 A CN 202010867590A CN 111875605 B CN111875605 B CN 111875605B
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- carboline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a preparation method and application of a bisamide compound I containing substituted pyrazole and beta-carboline units. By reacting beta-carboline compounds with 1-methyl-3-substituent-4-chloropyrazole-5-carbonyl chloride. The bisamide compound containing the substituted pyrazole and beta-carboline units has excellent antitumor effect on tumor cells, and can be used for preparing antitumor cell medicines.
Description
Technical Field
The invention relates to the field of medicines, in particular to preparation and application of a bisamide compound containing substituted pyrazole and beta-carboline units.
Background
In recent years, the incidence of cancer has been on the rise. Therefore, the search for effective anticancer drugs and therapeutic methods is one of the hot areas of research in the medical field.
Substituted pyrazole group is an important heterocycle, substituted pyrazole derivatives have wide application in the field of pharmaceutical industry, and in recent years, some pyrazole derivatives have been reported to have good inhibitory action on tumor cells, such as analgesic antipyrine and the like.
Carboline compounds are also important heterocyclic compounds, and carboline derivatives also have good anti-tumor effect.
Therefore, in order to find out a drug having a better antitumor effect from heterocyclic compounds, a substituted pyrazole unit is combined with a carboline fragment. The invention discloses a bisamide compound containing substituted pyrazole and beta-carboline units with medicinal value.
Disclosure of Invention
The invention aims to provide a bisamide compound containing substituted pyrazole and beta-carboline units, which has good anti-tumor activity on tumor cells.
Another object of the present invention is to provide a process for the preparation of the above compounds.
The invention also aims to provide the application of the compound in preparing anti-tumor cell medicines.
In order to solve the technical problems, the invention provides a bisamide compound containing substituted pyrazole and beta-carboline units, which has a structure shown in the following general formula I,
preferably, the bisamide compound containing substituted pyrazole and beta-carboline units has the following structure:
the invention provides a preparation method of the bisamide compound containing the substituted pyrazole and beta-carboline units, which is characterized by comprising the following reaction steps:
the intermediate beta-carboline compound is synthesized by a method of a reference literature (Chin.J.org.chem.2016,36,1431), and the intermediate 1-methyl-3-substituent-4-chloropyrazole-5-carbonyl chloride is synthesized by a method of a reference literature (Chin.J.org.chem.2017,37,1844).
The compound of the general formula I shows better anti-tumor effect on human gastric cancer cells SGC-7901.
The bisamide compound containing substituted pyrazole and beta-carboline units disclosed by the invention has obvious anti-tumor activity on human gastric cancer cells SGC-7901, and therefore, can be used for preparing anti-tumor cell medicines.
Detailed Description
To facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. These examples are provided for illustrative purposes only and are not intended to limit the scope or the principles of the invention.
Example 1:
4mmol of intermediate IIa and 3mL of triethylamine are added into a reaction bottle and dissolved in 50mL of tetrahydrofuran, 5mmol of intermediate IIIa is added under the ice bath condition, and then the mixture is reacted for 5 hours under the ice bath condition. The crude product obtained by evaporating the solvent is purified by silica gel column chromatography to obtain a target compound Ia; 1 H NMR:δ11.82(s,1H,NH),8.87(t,1H,J＝6.0Hz,CONH),8.82(t,1H,J＝6.0Hz,CONH),8.80(s,1H,Ar-H),8.41(d,1H,J＝7.6Hz,Ar-H),8.12(d,2H,J＝8.8Hz,Ar-H)7.89(d,2H,J＝8.8Hz,Ar-H),7.69(d,1H,J＝8.0Hz,Ar-H),7.59(t,1H,J＝7.6Hz,Ar-H),7.53(d,2H,J＝8.4Hz,Ar-H),7.31(t,1H,J＝7.2Hz,Ar-H),7.16(d,2H,J＝8.8Hz,Ar-H),3.87(d,6H,J＝2.8Hz,CH 3 ),3.63-3.66(m,2H,CH 2 ),3.56-3.59(m,2H,CH 2 ).
example 2:
5mmol of intermediate IIb and 20mmol of pyridine are added into a reaction bottle and dissolved in 35mL of dichloromethane, 5mmol of intermediate IIIa is added under ice bath condition, and then the mixture is reacted for 15 hours under ice bath condition. Evaporating the solvent to obtain a crude product, and purifying by silica gel column chromatography to obtain a target compound Ib; 1 H NMR:δ11.91(s,1H,NH),8.77(t,1H,J＝6.0Hz,CONH),8.71(t,1H,J＝5.6Hz,CONH),8.68(s,1H,Ar-H),8.34(d,1H,J＝8.0Hz,Ar-H),7.82(d,2H,J＝8.8Hz,Ar-H)7.63(d,1H,J＝8.0Hz,Ar-H),7.58(d,1H,J＝8.0Hz,Ar-H),7.54(d,2H,J＝8.4Hz,Ar-H),7.28(t,1H,J＝7.6Hz,Ar-H),3.94(s,3H,CH 3 ),3.46-3.50(m,2H,CH 2 ),3.36-3.41(m,2H,CH 2 ),2.83(s,3H,CH 3 ),1.83-1.86(m,2H,CH 2 ).
example 3:
10mmol of intermediate IIc and 3mL of triethylamine are added into a reaction bottle and dissolved in 50mL of dichloromethane, 12mmol of intermediate IIIb is added under ice bath condition, and then the mixture is reacted for 7 hours under ice bath condition. Evaporating the solvent to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain a target compound Ic; 1 H NMR:δ11.80(s,1H,NH),8.87(t,1H,J＝6.4Hz,CONH),8.78(s,1H,Ar-H),8.46(t,1H,J＝6.0Hz,CONH),8.40(d,1H,J＝8.0Hz,Ar-H),8.15(d,2H,J＝8.4Hz,Ar-H)7.69(d,1H,J＝8.4Hz,Ar-H),7.59(t,1H,J＝8.0Hz,Ar-H),7.31(t,1H,J＝8.0Hz,Ar-H),7.19(d,2H,J＝8.8Hz,Ar-H),3.90(s,3H,CH 3 ),3.84(s,3H,CH 3 ),3.46-3.51(m,2H,CH 2 ),3.35-3.40(m,2H,CH 2 ),2.12(s,3H,CH 3 ),1.80-1.86(m,2H,CH 2 ).
example 4:
9mmol of intermediate IId and 30mmol of sodium acetate are added into a reaction bottle and dissolved in 35mL of acetonitrile, 10mmol of intermediate IIIb is added under the ice bath condition, and the mixture is heated and refluxed for reaction for 13 hours. Evaporating the solvent to obtain a crude product, and purifying the crude product through silica gel column chromatography to obtain a target object Id; 1 H NMR:δ11.79(s,1H,NH),8.77(s,1H,Ar-H),8.71(t,1H,J＝6.0Hz,CONH),8.39-8.42(m,2H,CONH and Ar-H),8.13(d,2H,J＝8.8Hz,Ar-H)7.69(d,1H,J＝8.4Hz,Ar-H),7.59(t,1H,J＝8.0Hz,Ar-H),7.31(t,1H,J＝7.6Hz,Ar-H),7.19(d,2H,J＝8.4Hz,Ar-H),3.90(s,3H,CH 3 ),3.80(s,3H,CH 3 ),3.41-3.46(m,2H,CH 2 ),3.29-3.32(m,2H,CH 2 ),2.11(s,3H,CH 3 ),1.60-1.69(m,4H,2×CH 2 ).
example 5:
determination of the Activity of a sample on tumor cells
The sample is measured by using a tetramethylazole blue colorimetric Method (MTT)The product has in vitro antitumor activity. The test cell is human gastric cancer cell SGC-7901. FTS was selected as a positive control. Preparing 4 × 10 cancer cells in exponential growth phase 3 Cell suspension of individual cells/mL, seeded in 96-well plates in CO 2 The culture was carried out in an incubator for 36 hours. Test solutions (10. mu.L) of test compounds were then added to the test wells at each concentration in parallel wells and an equal amount of DMSO was used as a blank in CO 2 After 24 hours of incubation in the incubator, the supernatant was discarded, and 10. mu.L of 5% MTT was added to each well and incubated for 4 hours. Then, the supernatant was aspirated, 100. mu.L of DMSO was added to each well, and after shaking with a shaker for 20 minutes, the OD value was measured at a wavelength of 570nm with a microplate reader, and the inhibition rate of the sample against tumor cells was calculated. The cell inhibition rate (negative control group OD value-test object group OD value)/negative control group OD value is multiplied by 100%, and the IC of the sample is calculated by a probability unit weighted regression method 50 The value is obtained.
TABLE 1 antitumor Activity data (IC) of Compounds Ia-Id 50 ,μM)
| Compound (I) | SGC-7901 |
| Ia | 1.77 |
| Ib | 4.52 |
| Ic | 0.17 |
| Id | 16.27 |
| FTS | 41.30 |
The antitumor activity test data (Table 1) show that the compounds Ia to Id have good inhibition effect on human gastric cancer cells SGC-7901, wherein the compound Ic has the best activity on SGC-7901 cells, and the IC thereof 50 The value was 0.17. mu.M.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited by the foregoing examples, which are provided to illustrate the principles of the invention, and that various changes and modifications may be made without departing from the spirit and scope of the invention, which is also intended to be covered by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (3)
1. A bisamide compound I containing substituted pyrazole and beta-carboline units is characterized by having a structure as follows:
2. the process for preparing the bisamide compounds I containing the substituted pyrazole and beta-carboline units as claimed in claim 1, which comprises the following steps:
3. the use of the bisamide-based compound I containing substituted pyrazole and beta-carboline units according to claim 1 for preparing an anti-tumor cell medicament, wherein: the bisamide compounds I containing substituted pyrazole and beta-carboline units according to claim 1, have an inhibitory effect on SGC-7901 tumor cells.
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